The monoamine neurotransmitter dopamine (DA) plays a major role in regulating motor behavior, learning, reward and emotion (1, 2). Many neurological/neuropsychiatric disorders implicate a hyper-dopaminergic state in the etiology and/or maintenance of the disease (2-5). For example, U.S. Publication 2005/0048042 describes modulation of dopamine levels in the treatment of schizophrenia and addictive disorders. Recent SPECT and PET studies have confirmed an abnormally heightened level of synaptic dopamine in schizophrenia (6, 7).
Regulation of synaptic dopamine (DA) levels is predominantly regulated through active re-uptake by the dopamine transporter (DAT). Although previous studies have suggested the functional modulation of DAT by the dopamine D2 receptor (8-11) the molecular pathway underlying this process is yet unidentified. As the D2 receptor is a member of the G-protein coupled receptor (GPCR) family, any D2 receptor induced modulations are traditionally thought to be a sole product of protein phosphorylation via downstream activation of a second messenger cascade. However, in recent years, traditional concepts have been challenged with the identification of direct protein-protein interactions between two structurally and functionally distinct receptor families (12, 13).
Certain drugs increase dopamine concentrations by preventing dopamine reuptake, leaving more dopamine in the synapse. An example is the widely abused stimulant drug, cocaine. Another example is methylphenidate, used therapeutically to treat childhood hyperkinesis and symptoms of narcolepsy.
PCT Publication WO930826 discloses cloning of a cDNA encoding a dopamine transporter. Cells transfected with the cloned cDNA were observed to acquire dopamine uptake ability with the uptake by such transfected cells inhibitable by various uptake-inhibiting drugs. U.S. Pat. No. 6,218,595 discloses dopamine transporter knockout mice. Cells from these mice were observed to have decreased dopamine uptake. However, neither of these patent documents disclose a practical means for modulating dopamine activity.
A compound that could modulate dopamine activity could be used for treatment of core attention deficits seen in acute schizophrenics as well as treating addictive disorders such as addictions to cocaine or amphetamine.
At present, there are very few compounds available that are safe for mammalian administration and are selective for a dopamine transporter or receptor. For example, U.S. Patent Publication 20040077706 describes heterocyclic compounds that may be used to modulate activity of monoamine neurotransmitters, specifically dopamine, serotonin or norepinepherine. The use of the compounds for treating a variety of neurological or neuropsychiatric disorders relating to dopamine activity is suggested. However, none of the described compounds are shown to be selective for dopamine receptors or transporters.
Dopamine plays a major role in addiction. Regulation of dopamine plays a crucial role in mental and physical health. Neurons containing the neurotransmitter dopamine are clustered in the midbrain in an area called the substantia nigra. In Parkinson's disease, dopamine-transmitting neurons degenerate and the disease is marked by a progressive loss of dopamine production. Dopamine is involved in the reinforcing effects of natural rewards and is implicated in obesity. Thus, dopamine is involved in many physiological processes. However, there are very few small molecule compounds that selectively affect dopamine activity without impacting on other neurotransmitters, particularly monoamine neurotransmitters such as serotonin. There is a need for compounds that selectively modulate dopamine neurotransmission in the treatment of neurological or neuropsychiatric disorders, conditions or diseases in mammals.
Another problem in the present treatment of neurological disorders is resistance to drug therapy, for example in clinically diagnosed cases of depression. Thus, there is a need for new compounds and products that can modulate dopamine neurotransmission.